The inhibitory effect of the nitric oxide donor spermine NONOate (SNN) upon the copper(II) sulfate-dependent oxidation of human low-density lipoprotein (LDL) occurred with concentrations as low as 2 fM. The concentration dependence of this inhibition was non-linear. Low concentrations of SNN (<4 fM) were only poorly effective at inhibiting LDL oxidation; however, a dramatic enhancement of inhibition occurred about 4 fM SNN. This behavior is quite different from that of conventional antioxidants such as butylated hydroxytoluene (BHT), which have a linear concentration dependence. Addition of the lipid hydroperoxide (LOOH) 13[S-(E,Z)]-hydroperoxy-9,11-octadecadienoic acid (5 fM) to LDL diminished the antioxidant effect of intermediate concentration of SNN (4 and 8 fM), but did not affect the high concentration of SNN (12 fM). We proposed that a direct reaction is occurring between nitric oxide and the peroxyl radical, forming an nitric oxide-lipid adduct. The formation of such an adduct would also prevent the regeneration of LOOH, thereby preventing transition metal ion-dependent reinitiation (an LOOH-dependent process). It is possible that the difference in the kinetic behavior of SNN and BHT can be explained by this mechanism.